Carfilzomib, which is the active ingredient in KYPROLIS®, is a peptide epoxy ketone proteasome inhibitor indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completion of the last therapy. Carfilzomib irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib has been shown to have antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. The compound has also been shown to inhibit proteasome activity in blood and tissue and delay tumor growth in models of multiple myeloma, hematologic, and solid tumors.
Peptide epoxy ketone proteasome inhibitors, such as carfilzomib, have proven difficult to formulate due to their low aqueous solubility. In addition, the proteasome inhibitors are very unstable. Thus, compositions comprising these compounds must typically be lyophilized before storage and reconstituted before use. Moreover, the reconstituted compositions are often not stable themselves (even under refrigerated conditions). As shown in Table 1, certain reconstituted KYPROLIS® compositions must be used within 24 hours after reconstitution because of their instability.
TABLE 1Storage Conditions ofStability*per ContainerReconstituted KYPROLISVialSyringeIV Bag (¶)Refrigerated24 hours24 hours24 hours(2° C. to 8° C.; 36° F. to 46° F.)Room Temperature 4 hours 4 hours 4 hours(15° C. to 30° C.; 59° F. to 86° F.)*Total time from reconstitution to administration should not exceed 24 hours.(¶) 5% Dextrose Injection, USP
The need to lyophilize a composition comprising a peptide epoxy ketone proteasome inhibitor presents challenges to healthcare professionals. For example, dosing errors frequently occur during reconstitution of such products, and safety risks are presented if the reconstitution is not conducted aseptically. Additionally, the product after reconstitution is not stable for more than 24 hr, a product with such stability and storage temperature restrictions poses a problem for convenient use in a clinical use setting. Furthermore, lyophilized products allow for a one time reconstitution and use per patient. This type of presentation does not allow for injecting multiple doses. Also any unused portion of the reconstituted composition must be discarded, which leads to drug wasting. For at least these reasons, there is a need for new pharmaceutical compositions of peptide epoxy ketone proteasome inhibitors that provide improved solubility and stability for the peptide epoxy ketone proteasome inhibitor, as well as for ready-to-use compositions that eliminate the need for reconstitution.